Abstract

Familial dilated cardiomyopathy (DCM) and familial hypertrophic cardiomyopathy (HOM) are considered the two most common causes of inherited cardiovascular diseases. Previously, it has been difficult to study these diseases in human models because of limited access to human cardiomyocytes and difficulty growing them. With the discovery of human induced pluripotent stem cells (iPSCs) and the increased efficiency and reproducibility of differentiating them into beating cardiomyocytes (iPSC-CMs), the landscape has dramatically changed. For the first time, it is now possible to create patient-specific and disease-specific cell lines to improve our understanding of the molecular mechanisms of DCM and HCM. Hence the major goals of this multidisciplinary R24 Resource-Related Research Project are (i) generation, (ii) characterization, (iii) sequencing, and (iv) distribution of cardiac iPSC lines. Over the next 5 years, we plan to create an iPSC bank of 600 lines derived from control individuals, HCM patients, and DCM patients. To accomplish these goals, we have assembled a truly collaborative team of investigators with expertise in cardiovascular medicine, iPSC biology, developmental biology, next generation sequencing (NGS) technology, population genetics, biomedical informatics, large-scale database repository, and business development. We propose the following 4 Specific Aims over the next 5 years:
Aim 1 : To generate 600 iPSC lines from controls, DCM, and HCM patients.
Aim 2 : To evaluate drug safety screening using iPSCs (clinical trial in a petri dish).
Aim 3 : To obtain genotype-phenotype information using DNA-seq and RNA-seq.
Aim 4 : To distribute IPSC lines and their genotype-phenotype data to academic community. In summary, we believe this R24 will address a national need and fulfill NHLBI's strategic vision of creating a novel biorepository (iPSC-genotype-phenotype) that is valuable to the broader scientific community. Given our expertise and track record, we are confident we can deliver on these milestones.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Resource-Related Research Projects (R24)
Project #
5R24HL117756-02
Application #
8838250
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Buxton, Denis B
Project Start
2014-04-15
Project End
2019-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost

  Institution

Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304

  Publications

Garg, Priyanka; Garg, Vivek; Shrestha, Rajani et al. (2018) Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes as Models for Cardiac Channelopathies: A Primer for Non-Electrophysiologists. Circ Res 123:224-243
Chang, Alex C Y; Chang, Andrew C H; Kirillova, Anna et al. (2018) Telomere shortening is a hallmark of genetic cardiomyopathies. Proc Natl Acad Sci U S A 115:9276-9281
Liu, Qing; Van Bortle, Kevin; Zhang, Yue et al. (2018) Disruption of mesoderm formation during cardiac differentiation due to developmental exposure to 13-cis-retinoic acid. Sci Rep 8:12960
Argenziano, Mariana; Lambers, Erin; Hong, Liang et al. (2018) Electrophysiologic Characterization of Calcium Handling in Human Induced Pluripotent Stem Cell-Derived Atrial Cardiomyocytes. Stem Cell Reports 10:1867-1878
Rhee, Siyeon; Chung, Jae I; King, Devin A et al. (2018) Endothelial deletion of Ino80 disrupts coronary angiogenesis and causes congenital heart disease. Nat Commun 9:368
Kooreman, Nigel G; Kim, Youngkyun; de Almeida, Patricia E et al. (2018) Autologous iPSC-Based Vaccines Elicit Anti-tumor Responses In Vivo. Cell Stem Cell 22:501-513.e7
Garg, Priyanka; Oikonomopoulos, Angelos; Chen, Haodong et al. (2018) Genome Editing of Induced Pluripotent Stem Cells to Decipher Cardiac Channelopathy Variant. J Am Coll Cardiol 72:62-75
Bot, Corina T; Juhasz, Krisztina; Haeusermann, Fabian et al. (2018) Cross - site comparison of excitation-contraction coupling using impedance and field potential recordings in hiPSC cardiomyocytes. J Pharmacol Toxicol Methods 93:46-58
Zhao, Ming-Tao; Shao, Ning-Yi; Hu, Shijun et al. (2017) Cell Type-Specific Chromatin Signatures Underline Regulatory DNA Elements in Human Induced Pluripotent Stem Cells and Somatic Cells. Circ Res 121:1237-1250
Liu, Qing; Jiang, Chao; Xu, Jin et al. (2017) Genome-Wide Temporal Profiling of Transcriptome and Open Chromatin of Early Cardiomyocyte Differentiation Derived From hiPSCs and hESCs. Circ Res 121:376-391

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